We are trying to calculate the relative binding-free energies of various drugs to the HIV aspartyl protease. We have chosen a series of closely related compounds for which both high resolution x-ray structures and binding affinities are available. We have found that uncertainties in the crystal coordinates can have significant effects on the calculations leading to large differences in the calculated binding energies for drugs that are very similar. We are considering a number of approaches to deal with this problem including MD simulations so as to allow the x-ray coordinated to relax.